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A recent study has shown how important microglia are to the development of the human brain.

Researchers have discovered that microglia are essential for controlling the number of cells in the brain that develop into neurons, which has improved our knowledge of brain development and diseases.

By Francis DamiPublished 7 months ago 4 min read
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Super-resolution photo of Microglia cells derived from human stem cells, showing actin filaments (cyan), the nucleus (magenta), and the mitochondria (yellow). In organoid models of the human brain, these microglia cells aid in the maturation of neurons.

An international group of researchers has discovered the critical role that the immune cells known as microglia—which serve as the brain's specialized defense team—play in the early stages of human brain development. To better understand how microglia affect brain cell growth and development, scientists have been able to replicate the complex environment found in the developing human brain through the incorporation of microglia into lab-grown brain organoids.

This work could have a profound effect on our knowledge of brain development and disorders and marks a major advancement in the creation of human brain organoids. On November 1, 2023, the research paper titled "iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer" was released in the journal Nature.

Scientists from A*STAR's Singapore Immunology Network (SIgN), led by Professor Florent Ginhoux, used state-of-the-art technology to create brain-like structures called organoids, also known as "mini-brains," in the lab to study microglia's critical role in early human brain development. The development of these brain organoids is very similar to that of the human brain. Nevertheless, microglia, an essential element of early brain development, were absent from earlier models.

To close this gap, scientists at A*STAR devised a novel technique for introducing cells that resembled microglia and were produced from the same human stem cells that were used to make the brain organoids. Not only did these newly added cells exhibit characteristics of authentic microglia, but they also had an impact on the growth of other brain cells in the organoids.

To find changes in protein, Dr. Radoslaw Sobota of A*STAR's Institute of Molecular and Cell Biology (IMCB) and his colleagues at the SingMass National Laboratory for Mass Spectrometry used a state-of-the-art quantitative proteomics approach. Their analysis further confirmed the study's findings by offering important insights into the protein composition of the organoids.

The identification of a distinct mechanism by which microglia communicate with other brain cells is what distinguishes this work. According to the study, microglia are essential for controlling the amount of cholesterol in the brain.

It was discovered that the microglia-like cells contained cholesterol-containing lipid droplets, which were released and absorbed by additional growing brain cells in the organoids. It has been demonstrated that this cholesterol exchange greatly promotes these brain cells' growth and development, particularly that of their progenitors.

The brain contains large amounts of cholesterol, which constitutes approximately 25% of the body's total cholesterol content and is vital to the structure and operation of neurons. Parkinson's disease and Alzheimer's disease are among the neurological conditions that have been connected to abnormal cholesterol metabolism.

Under the direction of Professor Markus Wenk, researchers from the Yong Loo Lin School of Medicine (NUS Medicine) Department of Biochemistry undertook the vital task of data acquisition, particularly in the field of lipidomics to gain important insights into the lipid composition and dynamics within the brain organoids containing microglia. This work is part of their investigation into the roles of lipids in brain development and disease.

Using these data, a different team under the direction of Associate Professor Veronique Angeli from the Department of Microbiology and Immunology at NUS Medicine discovered that cholesterol has an impact on the maturation and growth of developing brain cells in human brain models. When the process by which microglia release cholesterol is inhibited, the organoid cells proliferate and eventually grow into larger brain models.

"The importance of microglia in brain development has long been recognized, but little is known about their specific function. Our team at the Department of Microbiology and Immunology has made a significant discovery that will change the way we think about cholesterol transport. Next, we'll investigate how to control the release of cholesterol to maximize brain development.

and delay or stop the development of neurological disorders," Assoc Prof. Veronique, who is also the NUS Medicine's Director of the Immunology Translational Research Programme, continued.

Furthermore, using proteomic and lipidomic analysis, Dr. Olivier Cexus of the University of Surrey and formerly of A*STAR gradually unraveled the intricate molecular interactions within the brain organoids. This has important implications for diseases and offers important insights into the metabolic cross-talks involved in brain development.

Our understanding of the functions of microglia and the molecular elements within brain organoids, as well as the implications for human health, has improved thanks to these combined efforts.

"Understanding the complex roles of microglia in brain development and function is an active area of research," stated Prof. Florent Ginhoux, Senior Principal Investigator at A*STAR's SIgN and Senior Author of the study. Our research contributes to our understanding of human brain development and may influence future research on brain disorders. This creates new avenues for investigating neurodevelopmental disorders and possible treatments in the future.

"There is currently a lack of tools to study how microglia interact with the developing brain," said Professor Jerry Chan, co-author of the study and senior consultant in the department of reproductive medicine at KK Women's and Children's Hospital as well as a senior clinician scientist with the National Medical Research Council.

This has made it more difficult to understand diseases linked to microglia, which are crucial for the early development of disorders like autism, schizophrenia, and neurodegenerative diseases like Parkinson's and Alzheimer's.

We now have the chance to investigate the intricate relationships that arise between microglia and neurons in the early stages of brain development thanks to the creation of these innovative microglia-associated brain organoids using same-donor pluripotent stem cells. As a result, this could make it possible for us to research how microglia function in disease settings and provide ideas for the timely development of novel treatments.

HumanityScienceNature
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Francis Dami

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